This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
EPA 0 021 580 and EPA 0 076 072 describe sulphonamide derivatives which are disclosed as having antiarrhythmic activity. A structurally distinct class of compounds has now been discovered, which have been found to have 5HT6 receptor antagonist activity. 5HT6 receptor antagonists are believed to be of potential use in to the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, cognitive memory enhancement e.g. for the treatment Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome).
The present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof: 
wherein:
P is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
A is a single bond, a C1-6alkylene or a C1-6alkenylene group;
R1 is halogen, C1-6alkyl optionally substituted by one or more halogen atoms, C3-6cycloalkyl, COC1-6alkyl, C1-6alkoxy, OCF3, hydroxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, C1-6alkanoyl, nitro, amino, C1-6alkylamino or diC1-6alkylamino, cyano or R1 is phenyl, naphthyl, a bicyclic heterocyclic ring or is a 5 to 7-membered heterocyclic ring each containing 1 to 4 heteroatoms selected from oxygen, nitrogen or sulphur;
n is 0, 1, 2, 3, 4, 5 or 6,
R2 is hydrogen, C1-6 alkyl or aryl C1-6 alkyl;
R3 is a group R5 or together with R5 forms a group (CH2)2O or (CH2)3O or R3 is linked to R2 to form a group (CH2)2 or (CH2)3;
R4 is xe2x80x94X(CH2)pxe2x80x94R6 where X is a single bond, CH2, O, NH or Nxe2x80x94 C1-6 alkyl and p is 0 to 6 and R6 is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulphur or oxygen, or R6 is NR7R8 where R7 and R8 are independently hydrogen, C1-6 alkyl or aryl C1-6 alkyl; and
R5 is hydrogen, halogen, C1-6alkyl, C3-6cycloalkyl, COC1-6alkyl, C1-6alkoxy, hydroxy, hydroxyC1-6alkyl, hydroxyC1-6alkoxy, C1-6alkoxyC1-6alkoxy, C1-6alkanoyl, nitro, trifluoromethyl, cyano or aryl.
C1-6 Alkyl groups, whether alone or as part of another group, may be straight chain or branched. Preferred alkyl groups are generally methyl and ethyl. As used herein the term aryl includes optionally substituted phenyl and naphthyl.
When P is a bicyclic heterocyclic ring suitable examples include benzothiophene, quinoline or isoquinoline. When P is a 5 to 7-membered heterocyclic ring suitable examples include thienyl, furyl, pyrrolyl, triazolyl, diazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrrolidinyl and pyrazinyl. The heterocyclic rings can be linked to the remainder of the molecule via any suitable carbon atom or, when present, a nitrogen atom. Suitable substituents for these rings include R5 groups as defined above.
Preferably P is phenyl, thiophene, benzothiophene or naphthyl.
Preferably A is a single bond, an ethylene group or a xe2x80x94CHxe2x95x90CHxe2x80x94 group. Most preferably A is a single bond.
When R1 is a heterocyclic group suitable examples include those listed above. Preferably R1 is halogen or C1-6alkyl optionally substituted by one or more halogen atoms, for example methyl or trifluoromethyl.
Preferably n is 0, 1, 2 or 3, particularly 1 or 2.
Suitably R2 is hydrogen or C1-6alkyl. Preferably R2 is hydrogen.
It will be appreciated that when R3/R5 groups are linked together the two groups must be attached to adjacent carbon atoms of the phenyl ring. Preferably R3 is a group R5, in particular hydrogen.
Preferably R4 is meta with respect to the sulphonamide linkage. Preferably X is a bond, p is 0 and R6 is an optionally substituted 5- to 7-membered heterocyclic ring. The heterocyclic rings can be linked to the remainder of the molecule via a carbon atom or, when present, a nitrogen atom. Optional substituents for these rings, which can be present on carbon and/or nitrogen atoms, include C1-6alkyl, in particular methyl. More preferably R4 is N-piperazine optionally substituted by C1-6alkyl, particularly unsubstituted piperazine.
Preferably R5 is C1-6alkoxy, most preferably methoxy. Preferably R5 is para with respect to the sulphonamide linkage.
A preferred meaning for P-A is benzo[b]thiophen-2-yl or benzo[b]thiophen-3-yl optionally substituted by one or two R1 groups, especially 5-chloro-3-methyl-benzo[2]thiophen-2-yl.
Particular compounds of the invention include: 4-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-5-(pyridin-2-yl)-2-thiophenesulfonamide, 2,5-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-thiophenesulfonamide, 4-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3-Bromo-5-chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzylsulfonamide, 2-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3-Bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-trans-styrenesulfonamide, 3,4-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3,5-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-[2,1 ,3]benzothiadiazole-4-sulfonamide, 5-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-2-benzothiophenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methyl-5-nitrobenzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-trifluoromethylbenzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-trifluoromethylbenzenesulfonamide, 2,5-Dimethoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Fluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Ethyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-tert-Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Isopropyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-tert-Amyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-trifluoromethoxybenzenesulfonamide, 4-n-Butoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonamide, 5-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-thiophenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1-naphthalenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-naphthalenesulfonamide, 5-(Dimethylamino)-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1-naphthalenesulfonamide, 4-Bromo-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide, 4-Methoxy-N-[4-methoxy-3-(4-methypiperazin-1-yl)phenyl]benzenesulfonamide, 4-n-Butyl-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Amino-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 2-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 2,3,4-Trichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2,5-dimethylbenzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methylbenzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2,3,5,6-tetramethylbenzenesulfonamide, 5-Chloro-2-methoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3-Fluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3,4-Difluoro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 4-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-nitrobenzenesulfonamide, 3-Chloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methylbenzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-8-quinolinesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-phenylbenzenesulfonamide, 3,4-Dimethoxy-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, N-[4-Methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3,5-dimethyl-4-isoxazolesulfonamide, 4-Bromo-N-[4-methoxy-3-(4-ethylpiperazin-1-yl)phenyl]benzenesulfonamide, 2,3-Dichloro-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-benzenesulfonamide, 5-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2-methylbenzenesulfonamide, 3-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]benzenesulfonamide, 3-Iodo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-4-methylbenzenesulfonanide, 5-Chloronaphthalene-2-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 5-Chloronaphthalene-1-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 4-Chloronaphthalene-1-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 7-Chloronaphthalene-1-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 5-Chloro-2-methylbenzo[b]thiophene-3-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, Benzofuran-2-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 1-Methyl-1H-indole-2-sulfonic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 5-Pyridin-2-ylthiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, N-(4-Methoxy-3-piperazin-1-ylphenyl)-3-trifluoromethylbenzenesulfonamide, 3-Iodo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 3,5-Dimethylisoxazole-4-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, 3,5-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, Naphthalene-1-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, 2-Bromo-5-chlorothiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, 2-Chloro-4-fluoro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 3-Bromo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 3-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 5-Chloronaphthalene-2-sulfonic acid(4-methoxy-3-piperazin-1-ylphenyl)amide, 4-Bromo-5-chlorothiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, 2,5-Dichlorothiophene-3-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide 4-Bromo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, 5-Chloro-2-methylbenzo[b]thiophene-3-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, 1-Methyl-1H-indole-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, Benzofuran-2-sulfonic acid (4-methoxy-3-piperazin-1-ylphenyl)amide, Naphthalene-2-sulfonic acid(4-methoxy-3-piperazin-1-ylphenyl)amide, 5-Chloronaphthalene-1-sulfonic acid(4-methoxy-3-piperazin-1-ylphenyl)amide, 4-Chloro-2,5-dimethyl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 3,4-Dichloro-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 3-Chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-4-methyl-benzenesulfonamide, 2-Trifluoromethyl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 4-Iodo-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, 4-tert-Butyl-N-(4-methoxy-3-piperazin-1-ylphenyl)benzenesulfonamide, Naphthalene-1-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, Thiophene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, 5-Chlorothiophene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, 5-Pyridin-2-ylthiophene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, 2,5-Dichlorothiophene-3-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, 4-Bromo-5-chlorothiophene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, 3-Bromo-5-chlorothiophene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, 4-Chloro-2,5-dimethyl-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide, Naphthalene-2-sulfonic acid [7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]amide. 3-Bromo-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide, 3,5-Dichloro-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide, 4-tert-Butyl-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N-[7-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl]benzenesulfonamide, 2,5-Dibromo-3,6-difluoro-N-(7-piperazin-1-yl-2,3-dihydrobenzofuran-5-yl)benzenesulfonamide, 4-Chloro-2,5-dimethyl-N-(7-piperazin-1-yl-2,3-dihydrobenzofuran-5-yl)benzenesulfonamide, 5-Chloro-3-methyl benzo [b]thiophene-2-sulphonic acid [3-(4-cyclopropylmethylpiperazin-1-yl)-4-methoxy-phenyl]amide, 5-Chloro-3-methyl benzo [b]thiophene-2-sulphonic acid [3-(4-benzyl-piperazin-1-yl)-4-methoxy-phenyl]-amide, 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid [4-hydroxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide, 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid [4-benzyloxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide, 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid [4-ethoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide, 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid [4-isopropoxy-3-(4-methylpiperazin-1-yl)-phenyl]-amide, 5-Chloro-3-methyl-benzo[b]thiophene-2-sulphonic acid [4-methoxy-3-(1-methylpyrrolidin-3-yloxy)-phenyl]-amide, Naphthalene-2-sulfonic acid [2-bromo-5-(4-methylpiperazin-1-yl)phenyl]amide 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [4-chloro-3-(4-methylpiperazin-1-yl)phenyl]amide, Naphthalene-2-sulfonic acid [4-bromo-3-(4-methylpiperazin-1-yl)phenyl]amide, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid[3-(2-dimethylaminoethoxy)-4-iodophenyl]amide, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [1-(2-dimethylaminoethyl)-2,3-dihydro-1H-indol-6-yl]amide, 1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole, 1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5-methoxy-6-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid[4-methoxy-2-methyl-3-(4-methylpiperazin-1-yl)phenyl]amide, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid[2-(2-hydroxyethyl)-4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide, 1-(5-Chloro-3-methylbenzo[b]thiophene-2-sulfonyl)-5-methoxy-4-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-indole hydrochloride, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid[3-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amide, 4-Bromo-N-[4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]benzenesulfonamide, 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [4-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]amide 5-Chloro-3-methylbenzo[b]thiophene-2-sulfonic acid [4-methoxy-3-(1-methylpiperidin-4-yl)phenyl]amide Naphthalene-2-sulfonic acid [3-(4-methylpiperazin-1-yl)phenyl]amide and pharmaceutically acceptable salts thereof.
The compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric and methanesulphonic.
Compounds of formula (I) may also form solvates such as hydrates, and the invention also extends to these forms. When referred to herein, it is understood that the term xe2x80x98compound of formula (I)xe2x80x99 also includes these forms.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms including diastereomers and enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises the coupling of a compound of formula (II): 
in which R1, n, P, and A are as defined in formula (I) or protected derivatives thereof and L is a leaving group with a compound of formula (III): 
in which R2, R3, R4 and R5 are as defined in formula (I) or protected derivatives thereof and optionally thereafter:
removing any protecting groups,
forming a pharmaceutically acceptable salt.
Suitable leaving groups include halogen, in particular chloro. The reaction of a compounds of formulae (II) and (III) is carried out by mixing the two reagents together, optionally in an inert solvent such as acetone. Such a reaction may be carried out in the presence of base.
Those skilled in the art will appreciate that it may be necessary to protect certain groups. Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Greene T. W. xe2x80x98Protective groups in organic synthesisxe2x80x99 New York, Wiley (1981). For example, suitable protecting groups for the piperazine group include BOC, COCCl3, COCF3 and methyl the latter of which may be removed by treatment with 1-chloroethyl chloroformate according to standard procedures.
N-substituted piperazines can be prepared by acylation or alkylation of the appropriate NH-piperazine compound according to standard procedures.
Compounds of formulae (II) and (III) are commercially available or may be prepared according to known methods or analogous to known methods.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
Compounds of formula (I) and their pharmaceutically acceptable salts have 5HT6 receptor antagonist activity and are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease (cognitive memory enhancement), sleep disorders (including disturbances of Circadian Rythym), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS.
Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders.
The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
When administered in accordance with the invention, no unacceptable toxicological effects are expected with the compounds of the invention.